Candidate: Dr. Stuart Friess is an Assistant Professor of Anesthesiology and Critical Care Medicine at the University of Pennsylvania (UPENN) and a Pediatric Critical Care Medicine Attending Physician at the Children's Hospital of Philadelphia (CHOP). The candidate has an established record of academic and research excellence, and the investigations proposed in this application are a natural progression of his work utilizing a large animal model to study traumatic brain injury (TBI) in children. Dr. Friess's long term career goal is to become a clinician-scientist in the area of pediatric TBI with independent funding to pursue research, mentor pediatric critical care fellows in basic science research, and translate findings from basic science research to new and effective TBI therapies for the pediatric population. Under the mentorship of Dr. Margulies, Dr. Friess has developed a comprehensive career development plan of graduate coursework in neurobiology and statistical analysis, as well as workshops, seminars, and journal clubs to ensure his transition to an independent clinician-scientist. Environment: The career development and research plan build upon an existing network of research and mentorship already in place at UPENN and CHOP, including the Center for Brain Injury and Repair. Dr. Friess has recruited an advisory committee of experts in TBI, large animal models, stroke, and pediatric critical care to ensure successful implementation of his career development plan and proposed investigations during the proposed career development award. Research: One of the principal goals of intensive care management of patients with TBI is the stabilization of derangements in cerebrovascular hemodynamics to avoid subsequent and additional neurotrauma. Therapies and interventions available to the pediatric intensivist to treat TBI are limited, and evidence for their efficacy is mainly based on adult or anecdotal data. Clinical trials in pediatric TBI are difficult to conduct due to the heterogeneous patient population and need for large multi-center studies. The pediatric TBI patient may be in a broad range of environments (ground or air transport, community hospital, adult trauma center, or pediatric tertiary care center) during the initial stabilization period depending on the geographic location of the injury event. During this time, the patient may be at greatest risk for developing secondary insults. Our goal is to develop inexpensive, easy-to-administer therapeutic interventions that can stabilize cerebrovascular hemodynamics during this critical time period and improve pediatric outcomes. We hypothesize that early stabilization of cerebral hypoperfusion following TBI with higher than currently accepted cerebral perfusion pressures and modulation of endothelin-1 signal transduction will reduce brain injury and improve functional outcomes. We have developed a clinically relevant pediatric porcine model of non-impact inertial head injury with subdural and subarachnoid hemorrhage, infarction, ischemia, and diffuse axonal injury, consistent with typical severe pediatric TBI. Using this model of TBI, we propose identifying clinical intracranial monitoring parameters that correlate with severity of neuropathology and neurobehavioral functional outcomes. We will then examine the roles of cerebral perfusion pressure (CPP) and modulation of endothelin-1 signal transduction in stabilizing cerebral hypoperfusion and reducing brain injury after TBI. Our major objective is to determine the benefits of CPP and endothelin-1 to cerebral hypoperfusion after pediatric head injury, and to develop early therapeutic interventions that will improve functional outcomes following pediatric TBI. Summary: These investigations will be integrated with mentoring meetings and course work in statistics and neurobiology to provide the candidate a pathway towards independence as a clinician investigator in pediatric neurocritical care medicine. The proposed studies will provide important preclinical data for future clinical studies, and a similar approach can be used to identify other neuroprotective interventions and therapeutics in future new investigator NIH research proposals.